Pancreatic islet transplantation offers a promising, minimally-invasive approach to restore normoglycemia and insulin independence in type 1 diabetics with hypoglycemic unawareness. However, its clinical applicability is compromised by the need for toxic immunosuppressive drugs, the need for islets from several pancreas donors to achieve insulin independence, and the long-term decline in islet function after transplantation. The protocols outlined in this application are multi-center, prospective, open-label trials that address these issues by assessing islet function and survival in 3 groups of patients with type 1 diabetes: 1) patients treated with a standardized steroid-free, calcineurin inhibitor sparing protocol (Clinical Islet Transplantation (CIT) protocol 07);2) patients treated with the standardized immunosuppressive protocol as well as the immunosuppressive drug deoxyspergualin (CIT protocol 03);and 3) patients with functional kidney allografts (CIT protocol 06). These protocols were originally initiated by the University of Minnesota, Northwestern University, and the University of California, San Francisco as part of the CIT consortium. Moving forward, the administration of the three will separate for logistic reasons as per NIH directive and RFA-DK-09-501, but the sites will continue to share the knowledge, expertise, and protocols that were initiated during the first five years of the CIT. RELEVANCE (provided by applicant): The proposed clinical protocols outlined in this application are designed to: 1) examine the effects of peritransplant addition of the immunosuppressive agent deoxyspergualin to a standardized immunosuppressive regimen in pancreatic islet transplantation in type 1 diabetic recipients;and 2) examine the outcomes of pancreatic islet transplantation in type 1 diabetic recipients with kidney allografts. We believe that the results of these studies will improve the efficacy of islet transplantation and contribute to the transition of clinical islet transplantation from clinical research to clinical care.